Abstract

Breast cancer is one of the most common malignancies globally. It accounts for approximately 15% of cancer-related deaths in Australian women. The orphan nuclear receptor liver receptor homolog-1 (LRH-1) promotes increased cell proliferation, motility and invasion in breast cancer cell lines. Additionally, high LRH-1 expression in human breast cancers is positively associated with estrogen receptor alpha status and aromatase activity. However, the role of LRH-1 in tumour growth is not well understood. Therefore, we aimed to generate a doxycycline (dox)-inducible mammary epithelial specific LRH-1 knock-in mouse in order to define the role of LRH-1 in mammary epithelial proliferation in vivo. In addition, the Dimethylbenz(a)anthracene (DMBA) induced mammary tumour model was utilized with the LRH-1 transgenic mice to determine the role LRH-1 plays in promoting mammary carcinogenesis. Given clear in vitro roles for LRH-1 in breast cancer cell proliferation, we hypothesise LRH-1 stimulates mouse mammary epithelial cell proliferation and promotes DMBA-mediated mammary tumorigenesis.

LRH-1 is known synergise with β-catenin to induce cyclin D1/E1 mediated cell proliferation in vitro. We analysed transcript levels of cyclin D1/E1 and show a significant increase in dox treated animals with or without DMBA. Finally, we demonstrate an increase in the oncogene β-catenin nuclear localisation in the dox treated animals with or without DMBA. Taken together, these data suggest that LRH-1 increases incidence of DMBA-induced mammary tumours. Further analyses on mechanism(s) mediated by LRH-1 are warranted to fully understand its role in mammary tumorigenesis.